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Summary: Background: The phase 2 ASUNCTIS study assessed the efficacy and safety of asunercept, a fully human CD95 (Fas) ligand-binding protein, in hospitalised patients with moderate-to-severe coronavirus disease (COVID-19) to assess the clinical benefit of CD95 ligand inhibition in this viral disease. Methods: In this open-label, multicentre, randomised, controlled, phase 2 trial, patients with COVID-19–induced pneumonia and respiratory deterioration were randomly assigned (1:1:1:1) in 12 Russian and Spanish hospitals using an interactive web-response system to receive standard of care (SOC) or SOC plus weekly asunercept 25 mg, 100 mg, or 400 mg, administered intravenously for up to 4 weeks, or until hospital discharge or death. The randomisation was stratified according to the respiratory support methods at the time of enrolment, corresponding to categories 4–6 of a clinical severity assessment scale comprising 9 levels that was recommended by the World Health Organization (WHO) at the time of the study. The main inclusion criterion was laboratory confirmed infection with SARS-CoV-2 OR typical radiological signs of SARS-CoV-2 infection. The primary endpoint was time from randomisation to clinical improvement on two consecutive days of at least one category on a WHO clinical severity assessment scale in the modified intent-to-treat population. All patients were subjected to regular safety analyses. This trial is registered with EudraCT (2020-001887-27) and ClinicalTrials.gov (NCT04535674). Findings: Between October 9, 2020, and September 24, 2021, 438 patients were randomly assigned to SOC (n = 110) or SOC plus asunercept 25 mg (n = 109), 100 mg (n = 109), or 400 mg (n = 110). The primary endpoint, time to sustained clinical improvement of one WHO category on two consecutive days from randomization, was in median [95% confidence interval]: 9 [6–12], 8 [7–12], 8 [7–11] and 13 [9–20] days for the 400 mg, 100 mg, 25 mg asunercept and SOC groups, respectively. The standard deviations for the 400 mg, 100 mg, 25 mg asunercept and SOC groups were 5.3, 4.9, 4.7 and 5 days, respectively. The observed differences between groups failed to reach statistical significance (one-sided p-value = 0.041). In total, 290 adverse events (AE) were registered in 145 patients who received at least one dose of the study treatment: 77 AEs in 37 (33.6%) patients in the SOC group, 80 AEs in 38 (34.9%) patients in the 25 mg group, 61 AEs in 35 (32.7%) patients in the 100 mg group and 72 AEs in 35 (32.1%) patients in the 400 mg group. There was no treatment-related death reported. In summary, asunercept was well tolerated at all doses tested and no specific safety signals were detected. Interpretation: The primary endpoint of time to sustained clinical improvement for distinct asunercept arms compared to SOC failed to meet statistical significance. The compound was safe and well tolerated. Funding: Apogenix GmbH, Heidelberg, Germany.

In low-risk Myelodysplastic Neoplasms (MDS), increased activity of apoptosis-promoting factors such as tumor necrosis factor (TNFα) and pro-apoptotic Fas ligand (CD95L) have been described as possible pathomechanisms leading to impaired erythropoiesis. Asunercept (APG101) is a novel therapeutic fusion protein blocking CD95, which has previously shown partial efficacy in reducing transfusion requirement in a clinical phase I trial for low-risk MDS patients (NCT01736436; 2012-11-26). In the current study we aimed to evaluate the effect of Asunercept therapy on the clonal bone marrow composition to identify potential biomarkers to predict response. Bone marrow samples of n = 12 low-risk MDS patients from the above referenced clinical trial were analyzed by serial deep whole exome sequencing in a total of n = 58 time points. We could distinguish a mean of 3.5 molecularly defined subclones per patient (range 2–6). We observed a molecular response defined as reductions of dominant clone sizes by a variant allele frequency (VAF) decrease of at least 10% (mean 20%, range: 10.5–39.2%) in dependency of Asunercept treatment in 9 of 12 (75%) patients. Most of this decline in clonal populations was observed after completion of 12 weeks treatment. Particularly early and pronounced reductions of clone sizes were found in subclones driven by mutations in genes involved in regulation of methylation (n = 1 DNMT3A, n = 1 IDH2, n = 1 TET2). Our results suggest that APG101 could be efficacious in reducing clone sizes of mutated hematopoietic cells in the bone marrow of Myelodysplastic Neoplasms, which warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: A previous phase 1 dose-escalation study in Taiwan indicated CAN008 (asunercept) with standard concurrent chemoradiotherapy (CCRT) improved progression-free survival (PFS) in newly diagnosed glioblastoma (GBM) patients. This study evaluates the efficacy of CAN008 in promoting overall survival (OS) and identifies genetic alterations associated with treatment responses. Methods: We compared OS of 5-year follow-ups from 9 evaluable CAN008 cohort patients (6 received high-dose and 3 received low-dose) to a historical Taiwanese GBM cohort with 164 newly diagnosed patients. CAN008 treatment response-associated genetic alterations were identified by whole-exome sequencing and comparing variant differences between response groups. Associations among patient survival, tumor mutational burden (TMB), and genetic alterations were analyzed using CAN008 cohort and TCGA-GBM dataset. Results: OS for high-dose CAN008 patients at 2 and 5 years was 83% and 67%, respectively, and 40.1% and 8.8% for the historical GBM cohort, respectively. Better OS was observed in the high-dose CAN008 cohort (without reaching the median survival) than the historical GBM cohort (median OS: 20 months; p = 0.0103). Five high-dose CAN008 patients were divided into good and poor response groups based on their PFS. A higher variant count and TMB were observed in good response patients, whereas no significant association was observed between TMB and patient survival in the newly diagnosed TCGA-GBM dataset, suggesting TMB may modulate patient CAN008 response. Conclusion: CAN008 combined with standard CCRT treatment prolonged the PFS and OS of newly diagnosed GBM patients compared to standard therapy alone. Higher treatment efficacy was associated with higher TMB.

Background: The phase 2 ASUNCTIS study assessed the efficacy and safety of asunercept, a fully human CD95 (Fas) ligand-binding protein, in hospitalised patients with moderate-to-severe coronavirus disease (COVID-19) to assess the clinical benefit of CD95 ligand inhibition in this viral disease., Methods: In this open-label, multicentre, randomised, controlled, phase 2 trial, patients with COVID-19-induced pneumonia and respiratory deterioration were randomly assigned (1:1:1:1) in 12 Russian and Spanish hospitals using an interactive web-response system to receive standard of care (SOC) or SOC plus weekly asunercept 25 mg, 100 mg, or 400 mg, administered intravenously for up to 4 weeks, or until hospital discharge or death. The randomisation was stratified according to the respiratory support methods at the time of enrolment, corresponding to categories 4-6 of a clinical severity assessment scale comprising 9 levels that was recommended by the World Health Organization (WHO) at the time of the study. The main inclusion criterion was laboratory confirmed infection with SARS-CoV-2 OR typical radiological signs of SARS-CoV-2 infection. The primary endpoint was time from randomisation to clinical improvement on two consecutive days of at least one category on a WHO clinical severity assessment scale in the modified intent-to-treat population. All patients were subjected to regular safety analyses. This trial is registered with EudraCT (2020-001887-27) and ClinicalTrials.gov (NCT04535674)., Findings: Between October 9, 2020, and September 24, 2021, 438 patients were randomly assigned to SOC (n = 110) or SOC plus asunercept 25 mg (n = 109), 100 mg (n = 109), or 400 mg (n = 110). The primary endpoint, time to sustained clinical improvement of one WHO category on two consecutive days from randomization, was in median [95% confidence interval]: 9 [6-12], 8 [7-12], 8 [7-11] and 13 [9-20] days for the 400 mg, 100 mg, 25 mg asunercept and SOC groups, respectively. The standard deviations for the 400 mg, 100 mg, 25 mg asunercept and SOC groups were 5.3, 4.9, 4.7 and 5 days, respectively. The observed differences between groups failed to reach statistical significance (one-sided p-value = 0.041). In total, 290 adverse events (AE) were registered in 145 patients who received at least one dose of the study treatment: 77 AEs in 37 (33.6%) patients in the SOC group, 80 AEs in 38 (34.9%) patients in the 25 mg group, 61 AEs in 35 (32.7%) patients in the 100 mg group and 72 AEs in 35 (32.1%) patients in the 400 mg group. There was no treatment-related death reported. In summary, asunercept was well tolerated at all doses tested and no specific safety signals were detected., Interpretation: The primary endpoint of time to sustained clinical improvement for distinct asunercept arms compared to SOC failed to meet statistical significance. The compound was safe and well tolerated., Funding: Apogenix GmbH, Heidelberg, Germany., Competing Interests: C Schoergenhofer and FH received honoraria from the sponsor for participation in the DSMB. CD is an employee of Saarmetrics GmbH which received payments from Apogenix GmbH for the analysis of the influence of asunercept on lymphocyte counts described in the manuscript. TL is a stakeholder of Saarmetrics GmbH which received payments from Apogenix GmbH for the analysis of the influence of asunercept on lymphocyte counts described in the manuscript. Saarmetrics received consulting fees for CD's and TL's work as consultants for Apogenix GmbH. AK and C Straub were employed by Apogenix GmbH at the time the study was conducted. JRPP, C Schoergenhofer, MB and BJ received funding for clinical trials from the sponsor. MK is an employee of Cytel Inc. and worked as a statistical consultant for Apogenix GmbH. HF, HW and TH are co-founders and shareholders of Apogenix GmbH. HW also worked as a consultant for Apogenix GmbH. JP, DdM and MT declare that they have no conflicts of interest., (© 2024 The Author(s).)

Background: A previous phase 1 dose-escalation study in Taiwan indicated CAN008 (asunercept) with standard concurrent chemoradiotherapy (CCRT) improved progression-free survival (PFS) in newly diagnosed glioblastoma (GBM) patients. This study evaluates the efficacy of CAN008 in promoting overall survival (OS) and identifies genetic alterations associated with treatment responses., Methods: We compared OS of 5-year follow-ups from 9 evaluable CAN008 cohort patients (6 received high-dose and 3 received low-dose) to a historical Taiwanese GBM cohort with 164 newly diagnosed patients. CAN008 treatment response-associated genetic alterations were identified by whole-exome sequencing and comparing variant differences between response groups. Associations among patient survival, tumor mutational burden (TMB), and genetic alterations were analyzed using CAN008 cohort and TCGA-GBM dataset., Results: OS for high-dose CAN008 patients at 2 and 5 years was 83% and 67%, respectively, and 40.1% and 8.8% for the historical GBM cohort, respectively. Better OS was observed in the high-dose CAN008 cohort (without reaching the median survival) than the historical GBM cohort (median OS: 20 months; p = 0.0103). Five high-dose CAN008 patients were divided into good and poor response groups based on their PFS. A higher variant count and TMB were observed in good response patients, whereas no significant association was observed between TMB and patient survival in the newly diagnosed TCGA-GBM dataset, suggesting TMB may modulate patient CAN008 response., Conclusion: CAN008 combined with standard CCRT treatment prolonged the PFS and OS of newly diagnosed GBM patients compared to standard therapy alone. Higher treatment efficacy was associated with higher TMB., Competing Interests: Conflicts of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kuo-Chen Wei reports financial support was provided by CANbridge Pharmaceuticals Inc. Gerald F. Cox and Fang-Min Huang report a relationship with CANbridge Pharmaceuticals Inc. that includes: employment., (© 2023 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Andriy Krendyukov, Christian GieffersApogenix AG, Heidelberg, GermanyCorrespondence: Andriy KrendyukovApogenix AG, Im Neuenheimer Feld 584, Heidelberg 69120, GermanyEmail andriy.krendyukov@apogenix.comAbstract: Glioblastoma is the most common and aggressive malignant tumor of the central nervous system. Despite the existing high unmet medical needs, the past few decades have seen no notable improvement in overall survival for glioblastoma patients. One active area of research to develop new therapeutic options for this disease is focusing on the CD95/Fas receptor and its ligand CD95L/FasL. It is now recognized that in addition to its role in programmed cell death, CD95/CD95L signaling is involved in a wide range of other apoptotic and non-apoptotic pathways directed toward T-effector cells and cells in the tumor microenvironment involved in tumor progression and invasiveness. Asunercept is a first-in-class recombinant glycosylated fusion protein, which has been designed to selectively bind to CD95L and therefore disrupt CD95/CD95L signaling. The current report provides a brief overview of the role of the CD95/CD95L signaling pathway in cancer pathogenesis and discusses how asunercept was designed to bind and neutralize CD95L and disrupt signaling thereby potentially improving outcomes in glioblastoma and other malignancies.Keywords: CD95/CD95L, apoptosis, asunercept, APG101, glioblastoma, immuno-oncology

Purpose: Glioblastoma is an aggressive malignant cancer of the central nervous system, with disease progression associated with deterioration of neurocognitive function and quality of life (QoL). As such, maintenance of QoL is an important treatment goal. This analysis presents time to deterioration (TtD) of QoL in patients with recurrent glioblastoma receiving Asunercept plus reirradiation (rRT) or rRT alone. Methods: Data from patients with a baseline and ≥ 1 post-baseline QoL assessment were included in this analysis. TtD was defined as the time from randomisation to the first deterioration in the EORTC QLQ-C15, PAL EORTC QLQ-BN20 and Medical Research Council (MRC)-Neurological status. Deterioration was defined as a decrease of ≥ 10 points from baseline in the QLQ-C15 PAL overall QoL and functioning scales, an increase of ≥ 10 points from baseline in the QLQ-C15 PAL fatigue scale and the QLQ-BN20 total sum of score, and a rating of "Worse" in the MRC-Neurological status. Patients without a deterioration were censored at the last QoL assessment. Kaplan–Meier estimates were used to describe TtD and treatment groups (Asunercept + rRT or rRT alone) were compared using the log-rank test. Results: Treatment with Asunercept + rRT was associated with significant improvement of TtD compared with rRT alone for QLQ-CL15 PAL overall QoL and physical functioning, and MRC Neurological Status (p ≤ 0.05). In the Asunercept + rRT group, QoL was maintained beyond progresison of disease (PoD). Conclusion: Treatment with Asunercept plus rRT significantly prolongs TtD and maintains QoL versus rRT alone in recurrent glioblastoma patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Asunercept showed promising clinical efficacy in anemic, transfusion-dependent patients with low and intermediate risk myelodysplastic syndrome. In this retrospective post hoc analysis, serum levels of biomarkers were measured in study patients focusing on cytokines associated with erythropoiesis, inflammation, apoptosis, bone marrow fibrosis, and inflammasome activity. Baseline serum biomarkers were correlated with treatment response in order to propose a hypothetical responder serum profile. Response to asunercept was associated with improved overall survival. Higher baseline values of interleukin-18 (IL-18), S100 calcium-binding protein A9 (S100A9) and soluble p53 were predictive of non-response to asunercept. Non-responding patients showed a distinct, pro-inflammatory serum cytokine profile which was persistent throughout the first half of the treatment phase and appeared unaffected by asunercept. Our post hoc analysis suggests that serum cytokine profiling based on IL-18, S100A9 and soluble p53 may represent an approach to identify and select low-risk myelodysplastic syndrome patients most likely to benefit from asunercept treatment. Asunercept (APG101) is a well-tolerated CD95-ligand inhibitor that showed promising efficacy in a prospective, single-arm phase I study in anemic, transfusion-dependent patients with low and intermediate risk myelodysplastic syndrome (MDS). In this retrospective post hoc analysis, serum levels of biomarkers were measured in study patients focusing on cytokines associated with erythropoiesis, inflammation, apoptosis, bone marrow fibrosis, and inflammasome activity. Baseline serum biomarkers were correlated with treatment response, in order to propose a hypothetical responder serum profile. After an updated median follow-up of 54 months (range 7–65), response to asunercept was associated with improved overall survival (at 3-years: 67% [95%CI 36–97] versus 13% [95%CI 0–36] in responders versus non-responders, respectively). Higher baseline values of interleukin-18 (IL-18), S100 calcium-binding protein A9 (S100A9) and soluble p53 were predictive of non-response to asunercept (area under the receiver operating characteristic curve 0.79–0.82). Furthermore, non-responding patients showed a distinct, pro-inflammatory serum cytokine profile which was persistent throughout the first half of the treatment phase and appeared unaffected by asunercept. Although prospective validation is required, our post hoc analysis suggests that serum cytokine profiling based on IL-18, S100A9 and soluble p53 may represent an approach to identify and select low-risk MDS patients most likely to benefit from asunercept treatment. [ABSTRACT FROM AUTHOR]